Chiara Calore

Clinicopathological profiles of progressive heart failure in hypertrophic cardiomyopathy

Aims Hypertrophic cardiomyopathy (HCM) is an important cause of heart failure-related disability over a wide range of ages. Profiles of severe progressive heart failure symptoms and death, or heart transplantation deserve more complete definition within large patient cohorts. Methods and results Clinical and morphological features of heart failure were assessed in 293 consecutive HCM patients over a median follow-up of 6 (inter-quartile range 2–11) years. Gross and histopathological features were analysed in 12 patients for whom the heart was available for inspection. Of the 293 patients, 50 (17%) developed severe progressive heart failure, including 18 who died or were transplanted. Three profiles of heart failure were identified predominantly associated with: (i) end-stage systolic dysfunction (ejection fraction <50%) (15; 30%); (ii) left ventricular (LV) outflow obstruction at rest (11; 22%); and (iii) non-obstructive with preserved systolic function (24; 48%). Overall, atrial fibrillation (AF) contributed to heart failure in 32 patients (64%) among the three profiles. Compared with other patients, those non-obstructive with preserved systolic function had earlier onset of heart failure symptoms mainly due to diastolic dysfunction, and the most accelerated progression to advanced heart failure and adverse outcome (P = 0.04). Thrombi were identified in the left atrial appendage of five gross heart specimens all belonging to patients with AF, including three of which were unrecognized clinically and had previously embolized. Extensive myocardial scarring with LV remodelling was evident in all end-stage patients; no or only focal scars were present in other patients. Conclusion Profiles of advanced heart failure in HCM are due to diverse pathophysiological mechanisms, including LV outflow obstruction and diastolic or global systolic ventricular dysfunction. Atrial fibrillation proved to be the most common disease variable associated with progressive heart failure. Recognition of the heterogeneous pathophysiology of heart failure in HCM is relevant, given the targeted management strategies necessary in this disease.

Structural and morphologic evaluation of a novel detergent–enzymatic tissue-engineered tracheal tubular matrix

OBJECTIVE We sought to bioengineer a nonimmunogenic tracheal tubular matrix of 6 cm in length and test its structural, functional, and immunologic properties in vitro and in vivo. METHODS Twelve-centimeter tracheal segments were harvested from Yorkshire boars. Half of each segment was subjected to a detergent-enzymatic method (containing sodium deoxycholate/DNase lavations) of decellularization for as many cycles as needed, and the other half was stored in phosphate-buffered saline at 4 degrees C as a control. Bioengineered and control tracheas were then implanted in major histocompatibility complex-unmatched pigs (allograft) or mice (xenograft) heterotopically for 30 days. Structural and functional analysis and immunostaining were performed after each detergent-enzymatic method cycle and transplantation. RESULTS Compared with control tracheas, bioengineered matrices displayed no major histocompatibility complex class I and II antigens after 17 detergent-enzymatic method cycles, without significant (P > .05) differences in their strain ability (rupture force, 56.1 +/- 3.3 vs 55.5 +/- 2.4 N; tissue deformation at 203% +/- 13% vs 200% +/- 8% or 12.2 +/- 0.8 vs 12 +/- 0.5 cm; and applied maximum force, 173.4 +/- 3.2 vs 171.5 +/- 4.6 N). Thirty days after implantation, significantly (P < .01) smaller inflammatory reactions (392 vs 15 macrophages/mm(2) and 874 vs 167 T lymphocytes/mm(2)) and P-selectin expressions (1/6 vs 6/6) were observed in both the xenograft and allograft models with bioengineered matrices compared with those seen with control tracheas. There was no development of anti-pig leukocyte antigen antibodies or increase in both IgM and IgG content in mice implanted with bioengineered tracheas. CONCLUSIONS Bioengineered tracheal matrices displayed similar structural and mechanical characteristics to native tracheas and excite no immune response to 30 days when implanted as allografts or xenografts. This method holds great promise for the future of tissue-engineered airway replacement.

Impact of the presence and amount of myocardial fibrosis by cardiac magnetic resonance on arrhythmic outcome and sudden cardiac death in nonischemic dilated cardiomyopathy

BACKGROUND Current risk stratification for sudden cardiac death (SCD) in nonischemic dilated cardiomyopathy (NIDC) relies on left ventricular (LV) dysfunction, a poor marker of ventricular electrical instability. Contrast-enhanced cardiac magnetic resonance has the ability to accurately identify and quantify ventricular myocardial fibrosis (late gadolinium enhancement [LGE]). OBJECTIVE To evaluate the impact of the presence and amount of myocardial fibrosis on arrhythmogenic risk prediction in NIDC. METHODS One hundred thirty-seven consecutive patients with angiographically proven NIDC were enrolled for this study. All patients were followed up for a combined arrhythmic end point including sustained ventricular tachycardia (VT), appropriate implantable cardioverter-defibrillator (ICD) intervention, ventricular fibrillation (VF), and SCD. RESULTS LV-LGE was identified in 76 (55.5%) patients. During a median follow-up of 3 years, the combined arrhythmic end point occurred in 22 (16.1%) patients: 8 (5.8%) sustained VT, 9 (6.6%) appropriate ICD intervention, either against VF (n = 5; 3.6%) or VT (n = 4; 2.9%), 3 (2.2%) aborted SCD, and 2 (1.5%) died suddenly. Kaplan-Meier analysis revealed a significant correlation between the LV-LGE presence (not the amount and distribution) and malignant arrhythmic events (P < .001). In univariate Cox regression analysis, LV-LGE (hazard ratio [HR] 4.17; 95% confidence interval [CI] 1.56-11.2; P = .005) and left bundle branch block (HR 2.43; 95% CI 1.01-5.41; P = .048) were found to be associated with arrhythmias. In multivariable analysis, the presence of LGE was the only independent predictor of arrhythmias (HR 3.8; 95% CI 1.3-10.4; P = .01). CONCLUSIONS LV-LGE is a powerful and independent predictor of malignant arrhythmic prognosis, while its amount and distribution do not provide additional prognostic value. Contrast-enhanced cardiac magnetic resonance may contribute to identify candidates for ICD therapy not fulfilling the current criteria based on left ventricular ejection fraction.

Phenotype and Differentiation Potential of Stromal Populations Obtained from Various Zones of Human Umbilical Cord: An Overview

Fibroblast-like cells with properties similar to mesenchymal stromal cells (MSCs) are present in human umbilical cord (hUC). In accordance with the international minimal criteria for defining multipotent mesenchymal stromal cells, hUC cells are designed MSCs being plastic adherent, positive to specific non hematopoietic lineage biomarkers, able to be both in vitro long term cultured and differentiated into osteoblasts, chondroblasts and adipocytes. In this review, a panoramic view of phenotypic characteristics of hUC cells derived from various UC parts are described. The high heterogeneity of extraction, culture and analysis procedures hinder the ability to precisely identify UC stromal cells. As a result, different phenotypic profiles are detectable not only among the cells obtained from the various parts of cord, but also inside the same UC regions, suggesting that UC-MSCs may represent an unique cell family whose components present various degree of stemness. However, in vitro and in vivo evidence indicates Whartons jelly as the best source of MSCs, because its cells present a wide range of potential therapeutic applications.

Contrast-enhanced cardiovascular magnetic resonance in primary and ischemic dilated cardiomyopathy.

Objectives Differentiation between primary dilated cardiomyopathy and ischemic cardiomyopathy has an important clinical significance. Contrast-enhanced cardiovascular magnetic resonance can play a role in this task, identifying myocardial scarring or fibrosis as presence of delayed enhancement. The aim of the present study was to evaluate the diagnostic potential of contrast-enhanced cardiovascular magnetic resonance in differentiating dilated cardiomyopathy from ischemic cardiomyopathy. Methods Contrast-enhanced cardiovascular magnetic resonance was performed in 100 patients with left ventricular dilatation and reduced systolic function: 24 had normal coronary arteries (dilated cardiomyopathy group) and 76 had significant coronary artery disease (ischemic cardiomyopathy group), with or without previous myocardial infarction. Results In the dilated cardiomyopathy group, only seven (29%) patients showed delayed enhancement and its pattern was characterized by mid-wall, patchy or diffuse location. All patients with ischemic cardiomyopathy and prior myocardial infarction (54 subjects) showed delayed enhancement with subendocardial (n = 4) or transmural (n = 50) extension. Among the 22 patients with ischemic cardiomyopathy but without previous myocardial infarction, 13 (59%) showed either subendocardial (n = 4) or transmural (n = 9) delayed enhancement. Conclusions Patterns of delayed enhancement are different in dilated cardiomyopathy and ischemic cardiomyopathy, reflecting the presence of scarring or various degrees of fibrosis in left ventricular myocardium. The presence of subendocardial or transmural delayed enhancement at contrast-enhanced cardiovascular magnetic resonance allowed distinction between dilated cardiomyopathy and ischemic cardiomyopathy with high sensitivity (88%) and specificity (100%). Integration of cardiovascular magnetic resonance results with angiographic information can be useful in the identification of pathogenic mechanisms underlying left ventricular dysfunction.

Genetic Modifiers of Duchenne Muscular Dystrophy and Dilated Cardiomyopathy

Objective Dilated cardiomyopathy (DCM) is a major complication and leading cause of death in Duchenne muscular dystrophy (DMD). DCM onset is variable, suggesting modifier effects of genetic or environmental factors. We aimed to determine if polymorphisms previously associated with age at loss of independent ambulation (LoA) in DMD (rs28357094 in the SPP1 promoter, rs10880 and the VTTT/IAAM haplotype in LTBP4) also modify DCM onset. Methods A multicentric cohort of 178 DMD patients was genotyped by TaqMan assays. We performed a time-to-event analysis of DCM onset, with age as time variable, and finding of left ventricular ejection fraction < 50% and/or end diastolic volume > 70 mL/m2 as event (confirmed by a previous normal exam < 12 months prior); DCM-free patients were censored at the age of last echocardiographic follow-up. Results Patients were followed up to an average age of 15.9 ± 6.7 years. Seventy-one/178 patients developed DCM, and median age at onset was 20.0 years. Glucocorticoid corticosteroid treatment (n = 88 untreated; n = 75 treated; n = 15 unknown) did not have a significant independent effect on DCM onset. Cardiological medications were not administered before DCM onset in this population. We observed trends towards a protective effect of the dominant G allele at SPP1 rs28357094 and recessive T allele at LTBP4 rs10880, which was statistically significant in steroid-treated patients for LTBP4 rs10880 (< 50% T/T patients developing DCM during follow-up [n = 13]; median DCM onset 17.6 years for C/C-C/T, log-rank p = 0.027). Conclusions We report a putative protective effect of DMD genetic modifiers on the development of cardiac complications, that might aid in risk stratification if confirmed in independent cohorts.

Prevalence and clinical meaning of isolated increase of QRS voltages in hypertrophic cardiomyopathy versus athlete's heart: relevance to athletic screening.

Intensiveathleticconditioningisassociatedwithphysiologiccardiacremodeling (known as “athletes heart”), consisting of augmented leftventricular (LV) mass due to increase of both cavity dimension andwall thickness, which are re flected on the electrocardiogram (ECG)mostfrequentlyasanincreaseofQRSvoltages[1,2].Becauseofthepar-tialoverlapofECGsignsofLVhypertrophy,athletesheartisofteninthedifferentialdiagnosiswithhypertrophiccardiomyopathy(HCM),whichis the leading cause of sports-related cardiac arrest in young athletes.Patients with HCM have a variety of ECG abnormalities, includingatrial enlargement, QRS left axis deviation, increase of QRS amplitudes,ST-segment and/or T-wave abnormalities, and pathologic Q waves [3].AccordingtotherecommendationsoftheEuropeanSocietyofCardiology,the ECG changes due to cardiac adaptat ion to physical exertion, predom-inantly the physiologic increase of QRS voltages, should not cause alarmand the athlete should be allowed to participate in competitive sportswithout additional evaluation [1]. Although this ECG interpretationapproach offers the potential to lower the traditional high number offalse-positives, whether and to what extent the increased speci ficityalter the ECG sensitivity for HCM remains to be established.The present study compared the ECG abnormalities associated withthe LV remodeling of HCM (nondilated, hypertrophic LV) and that ofathletes heart (augmented LV mass due to increase of both cavity di-mensionandwallthickness),withparticularreferencetotheprevalence,clinicalsignificance,andrelevancetoscreeningoftheECGpatternofiso-lated increase of QRS voltages. The main study objective was to evaluatethe risk to miss a diagnosis of HCM by interpreting as normal the ECGpattern of isolated increase of QRS amplitude in highly trained athletes.The HCM population included 247 consecutive patients (181 males;age 39 ± 14 years, range 15–65 years). The diagnosis of HCM wasbased on the presence of a hypertrophied and nondilated left ventriclein the absence of other diseases that could produce the magnitude ofhypertrophy evident. Echocardiographic criteria for diagnosis were amaximal LV wall thickness (LVWT) ≥ 15 mm in adult index patientsand ≥13 mm in adult relatives [4,5]. The athletes population includeda series of 133 Caucasian healthy, highly trained athletes (116 males;age 27 ± 6 years, range 15 –65 years) who fulfilled the echocardio-graphic criteria for augmented LV mass de fined according to Devereuxet al. as ≥134 g/m

A founder MYBPC3 mutation results in HCM with a high risk of sudden death after the fourth decade of life

Background Mutations in the cardiac myosin binding protein C (MYBPC3) gene account for a significant proportion of patients affected with hypertrophic cardiomyopathy (HCM). The aim of this study was to evaluate the penetrance and the impact of a frequent founder MYBPC3 mutation on HCM clinical expression and prognosis. Methods and results Mutation screening of MYBPC3 gene was performed in 97 HCM probands. Nineteen (19.5%) resulted to be carriers of the founder p.F305Pfs*27 mutation and other 45 mutation carriers were identified during the evaluation of 14 families. Eleven (38%) mutation carriers were diagnosed between ages 30 years and 40 years. Disease penetrance was incomplete (64.4%), age-related and was greater in men than women (85% vs 48%, p=0.009). Probands carrying the founder mutation exhibited highest prevalence of non-sustained ventricular tachycardia (63% vs 22%, p=0.003; 63% vs 23%, p=0.01) and implantable cardioverter-defibrillator (58% vs 17%, p=0.001; 58% vs 18%, p=0.005) when compared with probands without MYBPC3 mutations or carrying other MYBPC3 mutations. Reduced survival due to sudden cardiac death (SCD) or aborted SCD occurred more frequently after the fourth decade of life in probands carrying p.F305Pfs*27 mutation than those without MYBPC3 mutations (32% vs 15%, p=0.01). Conclusions p.F305Pfs*27 mutation carriers have a high probability to develop the disease between ages 30 years and 40 years with a significant major risk if they are men. This founder mutation is associated with an increase of SCD/aborted SCD events after the fourth decade of life.These findings are of relevant importance for management and clinical decision-making in patients with HCM.

Functional changes in Becker muscular dystrophy: implications for clinical trials in dystrophinopathies.

We performed a 1-year longitudinal study of Six Minute Walk Test (6MWT), North Star Ambulatory Assessment (NSAA), and timed function tests in Becker muscular dystrophy (BMD). Skeletal muscle dystrophin was quantified by immunoblot. We grouped deletions ending on exon 45 (“del 45-x”, n = 28) or 51 (“del x-51”, n = 10); isolated exon 48 deletion (“del 48”, n = 10); and other mutations (n = 21). Only patients in the “del 45-x” or “other” groups became non-ambulatory (n = 5, log-rank p = n.s.) or unable to run (n = 22, p < 0.001). All measures correlated positively with dystrophin quantity and negatively with age, and were significantly more impaired in the “del 45-x” and “other” groups. After one year, NSAA score decreased significantly (−0.9 ± 1.6, p < 0.001); in the “del 45-x” group, both NSAA (−1.3 ± 1.7, p = 0.001) and 6MWT (−12 ± 31 m, p = 0.059) decreased. We conclude that patients with “del x-51” or “del 48” mutations have mild or asymptomatic BMD, while “del 45-x” mutations cause comparatively severe weakness, and functional deterioration in 1 year. Furthermore, exon 51 skipping could be more effective than exon 45 skipping in Duchenne muscular dystrophy.

Accuracy of the ECG for differential diagnosis between hypertrophic cardiomyopathy and athlete’s heart: comparison between the European Society of Cardiology (2010) and International (2017) criteria

Background Interpretation of the athlete’s ECG is based on differentiation between benign ECG changes and potentially pathological abnormalities. The aim of the study was to compare the 2010 European Society of Cardiology (ESC) and the 2017 International criteria for differential diagnosis between hypertrophic cardiomyopathy (HCM) and athlete’s heart. Methods The study populations included 200 patients with HCM and 563 athletes grouped as follows: ‘group 1’, including normal ECG and isolated increase of QRS voltages, which are considered non-pathologic according to ESC and International criteria; ‘group 2’, including left atrial enlargement or left axis deviation in isolation and Q-waves with an amplitude ≥4 mm but <25% of the ensuing R-wave and a duration <0.04 s which are considered pathologic according to the ESC but not according to the International criteria; and ‘group 3’, including abnormalities which are considered pathologic according to ESC and International criteria. Results Overall, the 2010 ESC criteria showed a sensitivity of 95.5% and a specificity of 86.9%. Considering group 2 ECG changes as normal according to the International criteria led to a statistically significant (p<0.001) increase of specificity to 95.9%, associated with a non-significant (p=0.47) reduction of sensitivity to 93%. Among patients with HCM, there was a significant increase of maximal left ventricular wall thickness from group 1 to 3 (p=0.02). Conclusions The use of 2017 International criteria is associated with a substantial increase in specificity and a marginal decrease in sensitivity for differential diagnosis between HCM and athlete’s heart.